This project has as its objective the exploration of possible means of minimizing permanent hearing loss caused by noise and ototoxic drugs through treatment based on improved understanding of cochlear metabolism and pathophysiology. It begins with the hypothesis that the early stages of cochlear injury represent a disturbance of the microhomeostasis and may be reversible by enhanced blood flow and oxygenation, greater availability of metabolites, or accelerated removal of waste products. This hypothesis will be tested in the guinea pig cochlea after noise exposure and ototoxic drug administration sufficient to cause slight depression of the cochlear potentials without hair cell loss. Cochlear perfusion will be carried out with artifical perilymph, with and without the addition of oxygen, glucose, CO2, or vasoactive drugs, while cochlear microphonic and action potentials are being recorded. Similar measurements will be made in animals which will receive plasma volume expanders, ergot alkaloids, increased CO2, etc. without cochlear perfusions. Parallel studies of cochlear biochemistry will be carried out to elucidate the processes involved in the actions of noise, aminoglycosides, diuretics and combinations of those agents on hearing. This aspect of the research will also focus on the quantitative determination of drug concentrations in cochlear fluids and tissues and on the assay of adenyl cyclase and cyclic AMP, in an effort to establish their roles in relation to cochlear injury by noise and ototoxic drugs.